Marys Medicine


Pii: s0040-4039(02)00893-6

Tetrahedron Letters 43 (2002) 4833–4836 A new route to 1,4-disubstituted
Jirˇı´ Verner,a Jan Tarabab and Milan Pota´cˇeka,* aDepartment of Organic Chemistry, Faculty of Science, Masaryk University of Brno, Kotla´rˇska´ 2, 611 37 Brno, Czech Republic bDepartment of Inorganic Chemistry, Faculty of Science, Masaryk University of Brno, Kotla´rˇska´ 2, 611 37 Brno, Czech Republic Received 15 February 2002; revised 3 May 2002; accepted 10 May 2002 Abstract—1,4-Disubstituted 5-thioxoperhydroimidazo[4,5-d]imidazol-2-ones were prepared by one-pot criss-cross cycloaddition
reactions of 1,4-disubstituted 1,4-diazabuta-1,3-dienes with HNCS and HNCO generated in situ from potassium salts by acetic
acid. 2002 Elsevier Science Ltd. All rights reserved.
Structures with carbamide fragments have a broad trimethylsilylisothiocyanate with symmetrical 1,4-diaza- spectrum of biological activity. For example, 1,3,4,6- buta-1,3-dienes derived from aromatic and aliphatic tetramethylperhydroimidazo[4,5 - d]imidazol - 2,5 - dione amines (Scheme 2). The criss-cross addition on 1a in
was successfully used as a day-time tranquilizer and THF with trimethylsilylisothiocyanate affords 1,4- was introduced into medical practice in 1979 under the one 4a in 53% yield, and its oxidation with 30% H O
gave 2a in 75% yield.4 Reaction of 1b with trimethyl-
Symmetrical compounds with this skeleton (2 or 4)
silylisothiocyanate (dioxane, 3 h) afforded 4b (24%) at
were prepared either by a condensation of N-substi- room temperature.4 tuted ureas with glyoxal under acidic catalysis or by a
criss-cross addition on 1.
For example, N-(t-butyl)urea with glyoxal and HCl
catalyst forms 2 in a 62% yield2 (Scheme 1).
Reactions of 1,4-diazabuta-1,3-dienes 1 are rare in the
literature. Thus, Sakamoto et al.3 described the reaction
of 1,1%-biisoquinolines with aryl and benzoyl iso-
Scheme 2.
On the other hand, criss-cross cycloadditions on 2,3-diazabuta-1,3-dienes are well documented. In 1917Bailey and Moore5 described the reaction between somearomatic aldazines and thiocyanic acid or cyanic acid inacetic acid. The reaction was carried out by a slowaddition of potassium thiocyanate or cyanate into asolution of the aldazine in acetic acid. Similarly Schantlet al.6 prepared criss-cross products from various Scheme 1.
aliphatic ketazines by a slow addition of an acetic acidsolution of the ketazine into aqueous potassium cya- Keywords: criss-cross; cycloaddition; glyoxalimine; 1,4-diazabuta-1,3- nate. The molar ratio of acetic acid and cyanate was 1:1, in slight excess over the azine. Such a modification was used in order to avoid exposure of the already 41211214; e-mail: † Dedicated to Professor Jaroslav Jonas on the occasion of his 65th formed criss-cross adduct to an acidic environment which would cause its decomposition.
0040-4039/02/$ - see front matter 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 4 0 - 4 0 3 9 ( 0 2 ) 0 0 8 9 3 - 6 J. Verner et al. / Tetrahedron Letters 43 (2002) 4833–4836 In our communication we would like to report a new butadienes 1ac were prepared from glyoxal and the
and quick method for the preparation of mixed deriva- corresponding amines.7 tives, 5-thioxoperhydroimidazo[4,5-d]imidazol-2-ones 3,
substituted at positions 1 and 4 (Scheme 3). To the best
When we tried to prepare criss-cross adducts from of our knowledge, this is the only method for the simple aliphatic or aromatic 1,4-diazabuta-1,3-dienes 1
synthesis of these substances.
and HNCS or HNCO according to Bailey's5 or
Shantl's6 method, only traces of the desired products
were obtained. In some cases, the major isolated
product was the corresponding salt of the amine due to
the instability of substituted 1,4-diazabuta-1,3-dienes 1
in acid (Scheme 4).
Slow addition of the substituted 1,4-diazabuta-1,3-diene
1 into potassium isocyanate dissolved in carefully dried
acetic acid, improved the procedure. Due to the large
difference in reactivity between HNCS and HNCO, we
were able to obtain mixed cycloadducts 3 (Scheme 3) in
a one-pot procedure, when substituted 1,4-diazabuta-
1,3-dienes 1 were added to a mixture of both acids. We
examined the influence of concentration, as well as
Scheme 3.
We attempted to synthesize these products by criss-cross cycloaddition of HNCS and HNCO with 1,4-di-substituted Scheme 4.
Table 1. Effect of reactant concentration ratio upon composition of the reaction mixture after reaction of 1a with HNCO
and HNCS
1a starting concentration c=0.1 mol/l (ambient temperature), 1 h
2a (mol%)
3a (mol%)
4a (mol%)
Overall yield [%] Table 2. Effect of temperature upon composition of the reaction mixture after reaction of 1a with HCNO and HCNS
1a starting concentration c=0.1 mol/l (c
=0.1 mol/l, c Temperature (°C) 2a (mol%)
3a (mol%)
4a (mol%)
Overall yield (%) Table 3. Composition of reaction mixtures after reaction of 1ac with mixtures of acids in ratio c
Overall yield (%) a 30 min, c =0.25 mol/l, c =0.25 mol/l, c =0.125 mol/l.
b Vigorous agitation.
J. Verner et al. / Tetrahedron Letters 43 (2002) 4833–4836 temperature, upon the composition of the reaction mix- ture from 1a with the mixture of HCNO and HCNS.
Results are summarized in Tables 1 and 2.
1. Lebedev, O. V.; Khmel'nitskii, L. I.; Epishina, L. V.; Suvorova, L. I.; Zaikonnikova, I. V.; Zimakova, I. E.; Based on the results shown in Table 1, the ratio of Kirshin, S. V.; Karpov, A. M.; Chudnovskii, V. S.; et al.
concentrations cHNCO/cHNCS=2 was used for further The Directed Search for Neutropic Agents; Riga, 1983; pp.
2. Bakibaev, A. A.; Akhmedzhanov, R. R.; Yagovkin, A.
The major products under these conditions were mixed Yu.; Novozheeva, T. P.; Filimonov, V. D.; Saratikov, A.
criss-cross cycloadducts 3, which were separated, for
S. Pharm. Chem. J. (Engl. Transl.) 1993, 27, 401–406;
analysis, on a silica gel column (CH Cl Khim. Farm. Zh. 1993, 27, 29–33.
and characterized.8 Compositions of final mixtures were 3. Sakamoto, M.; Tomimatsu, Y.; Miyazawa, K.; Tokoro, K.
analyzed by 1H NMR spectra and the results are pre- Yakugaku Zasshi. 1972, 92, 1462–1467; Chem. Abstr. 1973,
sented in Table 3.
78, 97610(v).
4. Takahashi, M.; Miyadai, S. Heterocycles 1990, 31, 883.
In the NMR spectrum of symmetrical molecules 2a and
5. Bailey, J. R.; Moore, N. H. J. Am. Chem. Soc. 1917, 39,
4a there was only one signal for the protons H-3a and
H-6a, as a singlet with double intensity, l=5.26 ppm 6. Schantl, J. G.; Gstach, H.; Hebeisen, P.; Lanznaster, N.
and l=5.66 ppm, respectively. In the mixed derivative Tetrahedron 1985, 41, 5525–5528.
3a, the signals of these protons differ in chemical shift
7. tom Dieck, H.; Renk, I. W. Chem. Ber. 1971, 104, 92–109.
(l=5.40 ppm, l=5.52 ppm), and their coupling con- 8. Melting points were measured on a Boetius Rapido stant 3JH3a–H6a=8.9 Hz suggests a cis orientation. The PHMK 73/2106 (Wa¯getechnik) instrument. TLC was car- second coupling with the proton at the neighboring ried out on Silufol (Kavalier); detection was made by nitrogen atom appears for only one of the H-3a and Fluotes Universal (Quazlampen, Hanau) or in I vapors.
H-6a proton signals.‡ This coupling with 3J NMR spectra were recorded on Bruker Avance 300.
Hz disappears after addition of D O. The stereochem- istry of the structure 3a has been proved by X-ray
analysis.9 The crystal packing of 3a is shown in Fig. 1.
Mp 290–292°C. 1H NMR (300 MHz, DMSO-d ): 1.16– 1.80 (m, 20H), 3.38–3.45 (m, 1H), 4.11–4.19 (m, 1H), 5.40 We propose that the substituted 1,4-diazabuta-1,3- (d, 1H, J=8.9 Hz), 5.52 (dd, 1H, J=8.9 Hz, J=2.0 Hz), dienes 1 react with the more reactive species in the
7.54 (s, 1H, CO-NH), 8.94 (s, 1H, CS-NH). 13C NMR
reaction mixture i.e. thiocyanic acid, forming an inter- (75.5 MHz, DMSO-d ): 24.7, 25.3, 28.6, 28.9, 30.8, 31.1, mediate (1+1 adduct), which then reacts with cyanic 51.2, 54.3, 67.5, 67.6 (OC-N-CH-CH-N-CS), 67.6 (OC-
acid present in excess. Under properly chosen condi- N-CH-CH-N-CS), 158.3 (CO), 181.0 (CS). MS (70 eV)
tions product 3 predominates and the reaction repre-
sents a facile method for the preparation of such a
m/z (%): 325 (5), 323 (20), [M]+ 322 (8), 167 (9), 166 (100), mixed product.
157 (16), 98 (63), 84 (75).
1,4 - Di(4 - methoxyphenyl) - 5 - thioxoperhydroimidazo[4,5 - d]-
imidazol-2-one (3b)
Mp 290–291°C (dec.). 1H NMR (300 MHz, DMSO-d ):
3.76 (s, 3H, OCH ), 3.79 (s, 3H, OCH ), 5.96 (d, 1H,
J=8.3 Hz, OC-N-CH-CH-N-CS), 6.04 (d, 1H, J=8.3
Hz, OC-N-CH-CH-N-CS), 6.93 (2H, d, J=8.6 Hz,
ArH), 6.98 (2H, d, J=8.6 Hz, ArH), 7.32 (2H, d, J=8.6
Hz, ArH), 7.45 (2H, d, J=8.6 Hz, ArH), 8.20 (s, 1H,
CO-NH), 9.72 (s, 1H, CS-NH). 13C NMR (75.5 MHz,
DMSO-d ): 55.3 (Ar-OCH ), 55.3 (Ar-OCH ), 69.5 (OC-
N-CH-CH-N-CS), 72.0 (OC-N-CH-CH-N-CS), 115.0
(Ar), 115.0 (Ar), 122.4 (Ar), 128.9 (Ar), 130.5 (Ar-N),
130.6 (Ar-N), 155.9 (Ar-O), 156.6 (Ar-O), 158.1 (CO),
182.0 (CS). MS (70 eV) m/z (%): 372 (8), 371 (21), 370
[M]+ (99), 311 (17), 267 (18), 253 (20), 222 (25), 221 (37),
205 (31), 190 (31), 165 (49), 150 (45), 149 (94), 134 (100).
one (3c)
Mp 259–260°C. 1H NMR (300 MHz, DMSO-d ): 1.33 (s,
9H, C-CH ), 1.56 (s, 9H, C-CH ), 5.42 (d, 1H, J=8.3 Hz,
OC-N-CH-CH-N-CS), 5.57 (dd, 1H, J=8.3 Hz, J=2.0
Hz, OC-N-CH-CH-N-CS), 7.50 (s, 1H, OC-NH), 8.86
Figure 1. Crystal packing of compound 3a.
(s, 1H, SC-NH). 13C NMR (75.5 MHz, DMSO-d ): 28.0
(OC-N-C(CH ) ), 28.3 (SC-N-C(CH ) ), 52.3 (OC-N-
‡ 1H NMR (300 MHz) Bruker Avance in DMSO-d , at 600 MHz in C(CH ) ), 55.6 (S
C-N-C(CH ) ), 68.2 (OC-N-CH-CH-
CD COCD both couplings are visible.
N-CS), 69.4 (OC-N-CH-CH-N-CS), 158.8 (CO), 182.0
J. Verner et al. / Tetrahedron Letters 43 (2002) 4833–4836 (CS). MS (70 eV) m/z (%): 273 (4), 272 (14), [M]+ 270 (100),
refined assuming a ‘ride-on' model. Data are deposited in 213 (10), 199 (42), 157 (25), 140 (42), 125 (36), 116 (28), 100 Cambridge Crystallographic Data Centre as supplementary publication number CCDC 179213.
9. The X-ray data of 3a were collected on a KUMA KM-4
The crystal structure is composed of 3a molecules and water
CCD kappa-axis diffractometer using a graphite monochro- which are bound into a two dimensional network by a matized Mo–Ka radiation (u=0.71073 A,). The structure system of four types of hydrogen bonds: N(6)H···O(51)= was solved by direct methods (Sheldrick, G. M. SHELX-97 C(5) (2.876 A,) between two enantiomers of the molecules program package; University of Go¨ttingen, 1997; Sheldrick, of 3a forming dimers. These dimers are further connected
G. M. SHELXTL V 5.1; Bruker AXS GmbH.) Non-hydro- by hydrogen bonds of water molecules through N(3)H···O gen atoms were refined anisotropically while hydrogen (2.868 A,), OH···O(51)C (2.755 A,), and OH···S(21) (3.263 atoms were inserted in calculated positions and isotropically


PLAN CONTRA LA Edita: Instituto Asturiano de Prevención de Riesgos Laborales. Autores: ÁREA DE SEGURIDAD EN EL TRABAJOJEFE DE ÁREA: Javier Rodríguez Suárez TÉCNICOS SUPERIORES DE PREVENCIÓN: César Fueyo Martín Esther López González José María Fernández Rueda Manuel Iglesias Fanjul Minerva Espeso Expósito Pablo Mantilla Gómez Diseño y maquetación: Prisma Gabinete de Diseño (Gisela Pérez).

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